Infant sudden death: Mutations responsible for impaired Nav1.5 channel trafficking and function

Ivan Gando, Jace Morganstein, Kundan Jana, Thomas V. McDonald, Yingying Tang, William A. Coetzee

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


Background: Two genetic variants in SCN5A, encoding the Nav1.5 Na+ channel α-subunit, were found in a 5-month-old girl who died suddenly in her sleep. The first variant is a missense mutation, resulting in an amino acid change (Q1832E), which has been described (but not characterized) in a patient with Brugada syndrome. The second is a nonsense mutation that produces a premature stop codon and a C-terminal truncation (R1944Δ). Methods and Results: To investigate their functional relevance with patch clamp experiments in transfected HEK-293 cells. The Q1832E mutation drastically reduced Nav1.5 current density. The R1944Δ C-terminal truncation had negligible effects on Nav1.5 current density. Neither of the mutations affected the voltage dependence of steady activation and inactivation or influenced the late Na+ current or the recovery from inactivation. Biochemical and immunofluorescent approaches demonstrated that the Q1832E mutation caused severe trafficking defects. Polymerase chain reaction cloning and sequencing the victim's genomic DNA allowed us to determine that the two variants were in trans. We investigated the functional consequences by coexpressing Nav1.5(Q1832E) and Nav1.5(R1944Δ), which led to a significantly reduced current amplitude relative to wild-type. Conclusions: These sudden infant death syndrome (SIDS)-related variants caused a severely dysfunctional Nav1.5 channel, which was mainly due to trafficking defects caused by the Q1832E mutation. The decreased current density is likely to be a major contributing factor to arrhythmogenesis in Brugada syndrome and the sudden death of this SIDS victim.

Original languageEnglish (US)
Pages (from-to)703-712
Number of pages10
JournalPACE - Pacing and Clinical Electrophysiology
Issue number6
StatePublished - Jun 2017


  • Brugada syndrome
  • Na Channels
  • channelopathies
  • sudden infant death syndrome

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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